Clinical PNI and metabolic disorders When the immune system overrides the selfish

brain Prof. Leo Pruimboom

President of the International Association for Clinical PNI

Associate Professor University of Graz (Austria)

Director European Master in Clinical PNI, University of Graz (Austria)

Februari 2012

"If we could give every individual

the right amount of nourishment

and exercise, not too little and not

too much, we would have found

the safest way to health."

Hippocrates 400 BC

3

“Nothing in biology makes sense without

evolution”

Theodosius Dobzhansky 1973

“Nothing in medicine makes sense without

biology”

Frits Muskiet 2005

If society would be the cause, why are

their still lean people??????????

The impact of the insulin resistance

syndrome in modern society

Conference Statements and outline

• Adaptive on the short term

• Protective while enough insulin

• Deleterious on the long term

• Based on false triggers

• A psychoneuroendocrinoimmunological

disease

• An evolutionary solution

• The study of origin

Not insulin resistance but

insulin resistance syndrome 1. Pima Indians Higher insulin sensibility >> Obese

2. Low insulin >> Obese

3. High Insulin >> BMR << Obese

4. City Africans >> IR >> Obese

5. Ice-landers << IR

6. Kashmir-Himalayas << IR << Obese

Zargar AH et al. Diab Res Clin Practice 2000, 47:135-146.

Swinburn BA, et al. J Clin Invest 1991, 88:168-173.

Unger RH Nature Medicine 2006, 12(1):56-57

Kahn BB, Flier JS: J Clin Invest 2000, 106(4):473-481.

People eat to much and do not exercise

But they do know that this behavior makes them ill.

So why do they eat too much and don´t engage in

exercise??

Engagement in

minimal estimated

amount of exercise

Medical Hypotheses

77 (2011) 708–713

If so many people react the same, it has to have been

“programmed” by evolution

9

- Concepts of health

and disease - Master

SdC -

10 Molecular Systems Biology 3:137

Offspring of Ad Libidum versus undernourished mothers.

Note; the adult UN offspring is shorter but fatter

Bernhard H. Breier,* Stefan O. Krechowec and Mark H. Vickers. Early life programming of obesity and the lazy phenotype.

Early Life Origins of Health and Disease, edited by E. Marelyn Wintour and Julie A. Owens.

©2006

High Glycemic Load

Insulin and cortisol toxicity

Meal frequency and HGL-Food

Guilherme

et al. Nature

reviews.

2009 (9); 367

– 377

Saltiel 2007)

Obesity and insulin

resistance Syndrome CVD

Diabetes type II

Mental disorders

Depression

Autoimmune diseases

Insulin resistance

Syndrome

Acne

PCOS

Alopecia

Skin tags

Pigmentación

Acanthosis nigricans

Myopia

Cancer

Gout and psuedogout

Secular increase of height

Paradontosis

Apnea

Atherosclerosis Insulin resistance, hypercholesterol and gram-negative bacterial infection; the bodies defense

Specific

Oral Cave

Koren 2010, PNAS

High cholesterol protects against bacterial infection at the account of

atherosclerosis

Ravnskov U. High cholesterol may protect against infections and

atherosclerosis. QJM. 2003 12;96(12):927-34.

Rauchhaus M, Coats AJ, Anker SD. The endotoxin-lipoprotein hypothesis.

Lancet. 2000 09/09;356(9233):930-3.

Kitchens RL, Thompson PA, Munford RS, O'Keefe GE. Acute inflammation

and infection maintain circulating phospholipid levels and enhance

lipopolysaccharide binding to plasma lipoproteins. J Lipid Res. 2003

12;44(12):2339-48.

Comparative Biochemistry and

Physiology Part A 136 (2003) 95–112

1. Hunter DJ. Diet, Body size and breast

cancer. Epidem Rev 1993; 15:110-32.

2. Stoll BA. Western diet, early puberty,

and breast cancer risk. Breast Cancer

Res Treat 1998;49:187-93.

3. Hankinson SE et al. Circulating

concentrations of insulin-like growth

factor-1 and risk of breast cancer.

Lancet 1998;351:1393-6

Hypoxie-Stress Reaction, Hypoxie induced

Factor 1 and Insulin Resistance Syndrome

Heel Spur Frey C Foot Ankle Int. 2007 Sep;28(9):996-9.

Epicondylitis lateralis Shiri et al. Am J Epidemiol. 2006 Dec 1;164(11):1065-74.

Epicondylitis madialis Shiri et al. Am J Epidemiol. 2006 Dec 1;164(11):1065-74.

Tendinopathy Gaida et al. Arthritis Rheum. 2009 Jun 15;61(6):840-9.

Achilles Tendinopathy Gaida et al. Med Sci Sports Exerc. 2009 Jun;41(6):1194-7.

Bursopathies Werner et al. J Occup Rehabil. 2005 Mar;15(1):37-46.

Chronic pain Ray et al. Pain. 2011 Jan;152(1):53-9.

Fibrosis Spencer et Am. J. Physiol Endoc. Met. 2010 Dec;299(6):E1016-27.

Divoux et al. Diabetes. 2010 Nov;59(11):2817-25

Keloid buliding Verma. Am J Clin Dermatol. 2010 Dec 1;11(6):433-6

Carpal Tunnel Syndr. Gell et al. J Occup Rehabil. 2005 Mar;15(1):47-55.

Rotator Cuff Tendinitis Wendelboe J Bone Joint Surg Am. 2004 Apr;86-A(4):743-7.

Migraine Takashima Brain Nerve. 2009 Oct;61(10):1143-53.

High IL-1

High IL-6

High TNF alfa High Central Pro-

inflammatory Profile

High NFkappaB

Lower IL-1

Lower IL-6

Lower TNF alfa Low Peripheral Pro-

inflammatory Profile

Lower NFkappaB

Non or hardly immune cell infiltration

Krüger , K.: T cell homing and exercise Exerc Immunol Rev 13:37-54, 2007

The shift from peripheral to central immune acivity

CURRENT SCIENCE, VOL. 95, NO. 2, 25 JULY

2008

Er

The phylogenetical oldest system

= The immune system

JOURNAL OF EXPERIMENTAL ZOOLOGY (MOL DEV EVOL) 306B:496–520

(2006)

Simultaneous appearance

(Big) Brain

High basal metabolic rate

Glucocorticoid Receptor

Complete pancreas (98% exocrine – 2%

endocrine)

Mechanisms of Ageing and

Development 130 (2009) 216–221

Adult chimpanzee

Human newborn

Homo Floresiensis

Curr Anthropol. 1995 Apr.;36(2):pp. 199-221

Homo sapiens

Comparative

Biochemistry and

Physiology - Part A:

Molecular &

Integrative

Physiology. 2003

9;136(1):5-15.

Humans

Diabetes 49:1341–1346, 2000

0

200

400

600

800

Fecal Elastase

Vegetarians

Omivores

0

5

10

15

20

Chymotrypsin

Vegetarians

OmnivoresJournal of Pediatric

Gastroenterology and Nutrition

38:224–226 © February 2004

ug/g stool

p<0.05

U/g stool

p<0.05

Legumes-Fibres

Kunnitz factors

Lipase/protease-

inhibitors

Lectins

Saponins

Bowman-Birk factors

Hypoinsulinemia causes pancreatic atrophy with fat replacement of the

exocrine pancreas in different species. These results indirectly show the

significant role of insulin on pancreatic exocrine function. However,

direct evidence is also available to highlight the key role of insulin. Both

endogenous and exogenous insulin evoke increases in pancreatic

enzyme synthesis and growth. Insulin is not only important in healthy

conditions, but is also involved in the regenerative processes during

pancreatitis. Human studies have also proved the necessity of insulin in

pancreatic exocrine function. In conclusion, insulin has long term effects

on the regulation of the biosynthesis of pancreatic digestive enzymes and short term effects on the stimulation of pancreatic secretion

Vena portaI Intermittent insulin

50% insulin

50% insulin Intact

Gap junction

23% blood

12,2% basic

insulin

25-35% blood

12,5-17,5%

basic insulin

Intrinsic repair of

acinar cells

Vena porta Continuous insulin

90% insulin

10% insulin

Resistance

Absence of

gap junction

23% blood

21% basic

insulin

25-35% blood

22,5-31%basic

insulin

Exogenic insulin

Repair acinar cells

Accumulation of

adipose tissue

Fatty heart

Trends Cogn Sci (Regul Ed ). 2005 05;9(5):250-7.

The youngest system Big Brain

The oldest system Immune system

Phylogenesis

Straub. J InternMed2010;267: 543–560

Brascha. Progress in Neuro-Psychopharmacology & Biological Psychiatry 30

(2006) 827–853

Physiology Danger

Energy distribution in Physiology

The immune system = not expensive in rest

L. Pruimboom / Medical Hypotheses 77

(2011) 708–713

Chrousos, G. P. Nat. Rev. Endocrinol. 5, 374–381 (2009)

- Concepts of health

and disease - Master 45

Muscle Brain

(13 kcal/kilo) (197 kcal/kilo)

Glucose

Fatty acids Heart

Proteins (570 kcal/kilo)

Creatine-P

Liver (216 kcal/kilo)

Kidney (420 kcal/kilo) Immune system

Gut (212 kcal/kilo) (27 kcal/kilo)

J InternMed2010;267: 543–560.

Very expensive

Protein turnover (%) during chronic and massive

acute immune activation

Loss of muscles and induction of NPBD

Adapted from Lochmiller,

OIKOS 88: 87–98. Copenhagen 2000

Wound healing and high costs

Immune activation = 380 – 1500 kcal

Deep tissue production = size dependent Hurd TA. Wound Care 2004.

Ord H. Br J Nurs 2007.

J InternMed2010;267: 543–560

Brain Behav Immun. 2011 01;25(1):1-5.

Famine (poor countries), IRS, LGI,

Autoinflammatory and Autoimmune diseases

Brain

Stable

-20% Liver - 40%

Kidneys

- 40%

Muscles -20/-40/-60%

AMERICAN

JOURNAL OF

HUMAN BIOLOGY

23:29–34 (2011) Immune

system

Inflammation

Vitamin A, D, DHA, EPA

Long term inflammation

leads to a non-permissive

brain syndrome with IR and

LR.

L. Pruimboom / Medical Hypotheses 77

(2011) 708–713

The reptile phenotype/loss of thryroid

function/hibernation

• Brain function: depression; poor memory; inability to

concentrate; mood swings; sleep disturbances; anxiety

• Skin/hair quality; dry skinn; puffy eyes; hair loss; coarse or brittle hair

• Reproductive functions; irregular menstruation; heavy

menstruation; infertility; birth defects; erectile dysfunction;

delayed ejeculation

• Circulation/respiratory functions: high cholesterol; high blood

pressure; congestive heart failure; Sleep apnea

• Muscle/joint function: muscle cramps; weakness; pain; deep

voice; horse voice; pins and needles in hands/feet

• Metabolic functions: heat/cold intolerance; weight gain;

constipation; general tiredness

Pruimboom L. Medical Hypotheses 2011

Pruimboom, L. Van Nature 2009

58

Clinical Psychoneuroimmunology

The science based on the film and not on the photo

Proximate medicine

Present

Loss of husband Sedentary life

Sugar addiction

Insulin Resistance syndrome

Central adiposity Lack of immune migration

Clinical PNI – Metamodel 1

The symptom

Causes

(nutrition, inactivity, lack of

sunshine, tabaco)

Non-complete

systemic

resolution

Non-complete

local resolution

Central appeal

of stress axes Energy allocation

disorders

Clinical PNI – Metamodel 1

The symptom

Causes (nutrition, inactivity, lack of sunshine,

tabaco)

Insulin

resistance

Cortisol

Resistance

LGI

Proximate

medicine

The symptom

Nutrition, inactivity, lack of sunshine, tabaco, shift work, ACE, CLS,

Insulin

resistance

SAM>HPA

Sterile Inflammation

Exocrine

pancreatic

insufficiency

Energy

distribuition

disorder Cortisol resistance

A

C

U

T

E

C

H

R

O

N

I

C Reptile

Phenotype

Symptom

Nutrition, inactivity, lack of sunshine, tabaco, shift work, ACE, CLS,

Cortisol/Insulin

resistance

SAM>>HPA

(Sub)Sterile Low

Grade

Inflammation

Exocrine

pancreatic

insufficiency

Energie

Deficiency NTIS

A

C

U

T

E

C

H

R

O

N

I

C Sedentary

Lifestyle

Increased

Protein turn

over

Causes of low grade inflammation, insulin

resistance syndrome and non

permissive brain disorder

Obesity Reviews. 2011;12(5):339-45

British Journal of

Nutrition (2010), 104,

724–728

Kangaroo meat versus

domesticated meat

The role of food in low

grade inflammation Kangaroo

Hybridised

meat

The study of origin

August 2011

Background: Recovering self-sufficiency in an “original

environment” during a short period of time

should be able to normalize insulin sensibility and

therefore inflammatory and metabolic biomarkers.

Individuals with pathologies based on “modern

lifestyle” should benefit of this intervention

Methodology: 10 persons lived for a period of 10 days in the

pyrenees during the summer of 2011. Searching for

food, water, shelter and day/nighttime biorhythm

were all part of the self-sufficiency study. Immunological and metabolic biomarkers (soft

endpoints) and SF36 questionnaire (hard endpoint)

were used as measurements (6, 3, 1 month

before start, day of study-start, end of study, 4 months after study). Food and water intake was constantly

monitored

Results: Their was a significant improvement of all biomarkers.

hsCRP was raised (as expected) after the study and

normalized 4 months later. Individuals with chronic

fatigue were and are symptom-less (n=2). Two subjects with metabolic syndrome are still in the normal range.

Quality of life was improved in all subjects after

4 months (SF36)

84

85

86

87

88

89

90

91

92

93

Glucose

11/08/11

21/08/11

21/12/11

P < 0,05

*

The study of origin; Pruimboom prep.

Pyrenees 2011

n=10 Glucose

0

1

2

3

4

5

6

Insulin

11/08/11

21/08/11

21/12/11

P < 0,05

*

The study of origin; Pruimboom prep.

Pyrenees 2011

n=10 Insulin

0

10

20

30

40

50

60

70

Triglicerides

11/08/11

21/08/11

21/12/11

P < 0,05

*

The study of origin; Pruimboom prep.

Pyrenees 2011

n=10 Triglicerides

0

0.5

1

1.5

2

2.5

3

3.5

hsCRP

11/08/11

21/08/11

21/12/11

*p < 0,05

**p<0,05

**

*

The study of origin; Pruimboom prep.

Pyrenees 2011

n=10 hsCRP

0

50

100

150

200

250

Cholesterol

11/08/11

21/08/11

21/12/11

P < 0,05

*

The study of origin; Pruimboom prep.

Pyrenees 2011

n=10 Cholesterol

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